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- EMDB-39427: Structure of the Caspase-8/cFLIP death effector domain assembly -

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Basic information

Entry
Database: EMDB / ID: EMD-39427
TitleStructure of the Caspase-8/cFLIP death effector domain assembly
Map data
Sample
  • Complex: Caspase-8/cFLIP death effector domain assembly
    • Protein or peptide: CASP8 and FADD-like apoptosis regulator subunit p43
    • Protein or peptide: Caspase-8 subunit p10
KeywordsFADD / caspase-8 / cellular FLICE-like inhibitory protein / Death effector domain / APOPTOSIS
Function / homology
Function and homology information


negative regulation of myoblast fusion / skeletal myofibril assembly / caspase-8 / death effector domain binding / syncytiotrophoblast cell differentiation involved in labyrinthine layer development / FasL/ CD95L signaling / skeletal muscle atrophy / TRAIL signaling / CD95 death-inducing signaling complex / regulation of skeletal muscle satellite cell proliferation ...negative regulation of myoblast fusion / skeletal myofibril assembly / caspase-8 / death effector domain binding / syncytiotrophoblast cell differentiation involved in labyrinthine layer development / FasL/ CD95L signaling / skeletal muscle atrophy / TRAIL signaling / CD95 death-inducing signaling complex / regulation of skeletal muscle satellite cell proliferation / ripoptosome / Defective RIPK1-mediated regulated necrosis / Apoptotic execution phase / TRAIL-activated apoptotic signaling pathway / Activation, myristolyation of BID and translocation to mitochondria / TRIF-mediated programmed cell death / TLR3-mediated TICAM1-dependent programmed cell death / Microbial modulation of RIPK1-mediated regulated necrosis / Regulation by c-FLIP / CASP8 activity is inhibited / Dimerization of procaspase-8 / regulation of necroptotic process / Caspase activation via Death Receptors in the presence of ligand / positive regulation of extracellular matrix organization / positive regulation of macrophage differentiation / positive regulation of glomerular mesangial cell proliferation / self proteolysis / response to cobalt ion / NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 / activation of cysteine-type endopeptidase activity / : / skeletal muscle tissue regeneration / death-inducing signaling complex / negative regulation of hepatocyte apoptotic process / CLEC7A/inflammasome pathway / negative regulation of necroptotic process / natural killer cell activation / : / tumor necrosis factor receptor binding / regulation of tumor necrosis factor-mediated signaling pathway / death receptor binding / positive regulation of hepatocyte proliferation / : / negative regulation of cellular response to transforming growth factor beta stimulus / TNFR1-induced proapoptotic signaling / RIPK1-mediated regulated necrosis / negative regulation of cardiac muscle cell apoptotic process / execution phase of apoptosis / pyroptotic inflammatory response / regulation of innate immune response / Apoptotic cleavage of cellular proteins / response to testosterone / positive regulation of proteolysis / B cell activation / cellular response to organic cyclic compound / protein maturation / macrophage differentiation / extrinsic apoptotic signaling pathway via death domain receptors / cellular response to nitric oxide / Caspase-mediated cleavage of cytoskeletal proteins / response to tumor necrosis factor / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / negative regulation of canonical NF-kappaB signal transduction / negative regulation of reactive oxygen species biosynthetic process / skeletal muscle tissue development / cysteine-type peptidase activity / keratinocyte differentiation / extrinsic apoptotic signaling pathway / enzyme activator activity / regulation of cytokine production / cellular response to epidermal growth factor stimulus / cellular response to dexamethasone stimulus / erythrocyte differentiation / T cell activation / positive regulation of interleukin-1 beta production / apoptotic signaling pathway / proteolysis involved in protein catabolic process / Regulation of NF-kappa B signaling / cellular response to estradiol stimulus / negative regulation of extrinsic apoptotic signaling pathway / Regulation of TNFR1 signaling / wound healing / NOD1/2 Signaling Pathway / neuron differentiation / Regulation of necroptotic cell death / positive regulation of neuron projection development / cellular response to insulin stimulus / cellular response to mechanical stimulus / positive regulation of neuron apoptotic process / lamellipodium / response to estradiol / heart development / peptidase activity / positive regulation of NF-kappaB transcription factor activity / cellular response to hypoxia / cell body / scaffold protein binding / protease binding / angiogenesis / positive regulation of canonical NF-kappaB signal transduction
Similarity search - Function
Caspase-8 / : / Death effector domain / Death effector domain / Death effector domain (DED) profile. / Death effector domain / Peptidase family C14A, His active site / Caspase family histidine active site. / Peptidase C14, caspase non-catalytic subunit p10 / Peptidase family C14A, cysteine active site ...Caspase-8 / : / Death effector domain / Death effector domain / Death effector domain (DED) profile. / Death effector domain / Peptidase family C14A, His active site / Caspase family histidine active site. / Peptidase C14, caspase non-catalytic subunit p10 / Peptidase family C14A, cysteine active site / Caspase family cysteine active site. / Caspase family p10 domain profile. / Peptidase C14A, caspase catalytic domain / Caspase, interleukin-1 beta converting enzyme (ICE) homologues / Peptidase C14, p20 domain / Caspase family p20 domain profile. / : / Caspase domain / Caspase-like domain superfamily / Death-like domain superfamily
Similarity search - Domain/homology
CASP8 and FADD-like apoptosis regulator / Caspase-8
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.49 Å
AuthorsLin S-C / Yang C-Y
Funding support Taiwan, 1 items
OrganizationGrant numberCountry
Other government Taiwan
CitationJournal: Nat Commun / Year: 2024
Title: Reverse hierarchical DED assembly in the cFLIP-procaspase-8 and cFLIP-procaspase-8-FADD complexes.
Authors: Chao-Yu Yang / Yi-Chun Tseng / Yi-Fan Tu / Bai-Jiun Kuo / Li-Chung Hsu / Chia-I Lien / You-Sheng Lin / Yin-Ting Wang / Yen-Chen Lu / Tsung-Wei Su / Yu-Chih Lo / Su-Chang Lin /
Abstract: cFLIP, a master anti-apoptotic regulator, targets the FADD-induced DED complexes of procaspase-8 in death receptor and ripoptosome signaling pathways. Several tumor cells maintain relatively high ...cFLIP, a master anti-apoptotic regulator, targets the FADD-induced DED complexes of procaspase-8 in death receptor and ripoptosome signaling pathways. Several tumor cells maintain relatively high levels of cFLIP in achieving their immortality. However, understanding the three-dimensional regulatory mechanism initiated or mediated by elevated levels of cFLIP has been limited by the absence of the atomic coordinates for cFLIP-induced DED complexes. Here we report the crystal plus cryo-EM structures to uncover an unconventional mechanism where cFLIP and procaspase-8 autonomously form a binary tandem DED complex, independent of FADD. This complex gains the ability to recruit FADD, thereby allosterically modulating cFLIP assembly and partially activating caspase-8 for RIPK1 cleavage. Our structure-guided mutagenesis experiments provide critical insights into these regulatory mechanisms, elucidating the resistance to apoptosis and necroptosis in achieving immortality. Finally, this research offers a unified model for the intricate bidirectional hierarchy-based processes using multiprotein helical assembly to govern cell fate decisions.
History
DepositionMar 11, 2024-
Header (metadata) releaseOct 30, 2024-
Map releaseOct 30, 2024-
UpdateOct 30, 2024-
Current statusOct 30, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_39427.png

Downloads & links

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Map

FileDownload / File: emd_39427.map.gz / Format: CCP4 / Size: 137.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 330 pix.
= 277.2 Å		0.84 Å/pix.
x 330 pix.
= 277.2 Å		0.84 Å/pix.
x 330 pix.
= 277.2 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.84 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.31
Minimum - Maximum-0.74898994 - 1.5024467
Average (Standard dev.)0.0021996964 (±0.049210776)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions330330330
Spacing330330330
CellA=B=C: 277.19998 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_39427_half_map_1.map
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Histogram

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Half map: #1

Fileemd_39427_half_map_2.map
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Sample components

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Entire : Caspase-8/cFLIP death effector domain assembly

EntireName: Caspase-8/cFLIP death effector domain assembly
Components
  • Complex: Caspase-8/cFLIP death effector domain assembly
    • Protein or peptide: CASP8 and FADD-like apoptosis regulator subunit p43
    • Protein or peptide: Caspase-8 subunit p10

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Supramolecule #1: Caspase-8/cFLIP death effector domain assembly

SupramoleculeName: Caspase-8/cFLIP death effector domain assembly / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: CASP8 and FADD-like apoptosis regulator subunit p43

MacromoleculeName: CASP8 and FADD-like apoptosis regulator subunit p43 / type: protein_or_peptide / ID: 1 / Number of copies: 8 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 20.878479 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MSAEVIHQVE EALDTDEKEM LLFLCRDVAI DVVPPNVRDL LDILRERGKL SVGDLAELLY RVRRFDLLKR ILKMDRKAVE THLLRNPHL VSDYRVLMAE IGEDLDKSDV SSLIFLMKDY MGRGKISKEK SFLDLVVELE KLNLVAPDQL DLLEKCLKNI H RIDLKTKI QKYKQSVQGA GTS

UniProtKB: CASP8 and FADD-like apoptosis regulator

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Macromolecule #2: Caspase-8 subunit p10

MacromoleculeName: Caspase-8 subunit p10 / type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 55.191648 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MDFSRNLYDI GEQLDSEDLA SLKFLSLDYI PQRKQEPIKD ALMLFQRLQE KRMLEESNLS FLKELLFRIN RLDLLITYLN TRKEEMERE LQTPGRAQIS AYRVMLYQIS EEVSRSELRS FKGGLQEEIS KCKLDDDMNL LDIFIEMEKR VILGEGKLDI L KRVCAQIN ...String:
MDFSRNLYDI GEQLDSEDLA SLKFLSLDYI PQRKQEPIKD ALMLFQRLQE KRMLEESNLS FLKELLFRIN RLDLLITYLN TRKEEMERE LQTPGRAQIS AYRVMLYQIS EEVSRSELRS FKGGLQEEIS KCKLDDDMNL LDIFIEMEKR VILGEGKLDI L KRVCAQIN KSLLKIINDY EEFSKERSSS LEGSPDEFSN GEELCGVMTI SDSPREQDSE SQTLDKVYQM KSKPRGYCLI IN NHNFAKA REKVPKLHSI RDRNGTHLDA GALTTTFEEL HFEIKPHDDC TVEQIYEILK IYQLMDHSNM DCFICCILSH GDK GIIYGT DGQEAPIYEL TSQFTGLKCP SLAGKPKVFF IQAAQGDNYQ KGIPVETASE EQPYLEMALS SPQTRYIPDE ADFL LGMAT VNNCVSYRNP AEGTWYIQSL CQSLRERCPR GDDILTILTE VNYEVSNKDD KKNMGKQMPQ PTFTLRKKLV FPSD

UniProtKB: Caspase-8

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.2 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
80.0 mMNaClsodium chloride
20.0 mM(HOCH2)3CNH2Tris
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 279 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
SoftwareName: EPU
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average electron dose: 72.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm / Nominal magnification: 165000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 246000
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.49 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 28464
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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